Various central nervous system disorders such as anxiety, depression etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. The actions of the neurotransmitter 5-hydroxytryptamine (5-HT) as a major modulatory neurotransmitter in the brain, are mediated through a number of receptor families termed 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7. Based on a high level of 5-HT6 receptor mRNA in the brain, it has been stated that the 5-HT6 receptor may play a role in the pathology and treatment of central nervous system disorders. In particular, 5-HT6 receptor selective ligands have been identified as potentially useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Such compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder. (See for ex. B. L. Roth et al., J. Pharmacol. Exp. Ther, 1994, 268, 1403-14120; D. R. Sibley et al., Mol. Pharmacol, 1993, 43, 320-327; A. J. Sleight et al., Neurotransmission, 1995, 11, 1-5; and A. J. Sleight et al., Serotonin ID Research Alert., 1997, 2 (3), 115-118).
Studies have found that a known 5-HT6 selective antagonist significantly increased glutamate and aspartate levels in the frontal cortex without elevating levels of noradrenaline, dopamine or 5-HT6. This selective elevation of certain neurochemicals is noted during memory and cognition, strongly suggests a role for 5-HT6 ligands in cognition (Dawson, L. A.; Nguyen, H. Q.; Li, P., British Journal of Pharmacology, 2000, 130 (1), 23-26). Animal studies of memory and leaming with a known selective 5-HT6 antagonist has some positive effects (Rogers, D. C.; Hatcher, P. D.; Hagan, J. J., Society of Neuroscience, Abstracts, 2000, 26, 680). A related potential therapeutic use for 5-HT6 ligands is the treatment of attention deficit disorders (ADD, also known as Attention Deficit Hyperactivity Disorder or ADHD) in children as well as adults. As 5-HT6 antagonists appear to enhance the activity of the nigrostriatal dopamine pathway and ADHD has been linked to abnormalities in the caudate (Ernst, M.; Zametkin, A. J.; Matochik, J. H.; Jons, P. A.; Cohen, R. M., Journal of Neuroscience, 1998, 18 (15), 5901-5907), 5-HT6 antagonists may attenuate attention deficit disorders. 5-HT6 antagonists have also been identified as potentially useful compounds for treatment of obesity. See for example, Bentley et al., Br. J Pharmac. 1999, Suppl 126; Bently et al., J. Psychopharmacol. 1997, Suppl A64, 255; Wooley et al., Neuropharmacology 2001, 41, 210-129; and WO02098878.
Pulmonary arterial hypertension (PAH) is a kind of progressive malignant disease which is characterized as increasing progressive pulmonary vascular resistance, finally leading to right heart failure and even death. With the development of deepening research in the pathogenesis of PAH, the treatment of PAH has broad prospects. 5-hydroxytryptamine (5-HT) used as a vasoactive substance was first proposed in 1955, which widely exists in animals, especially in the cardiovascular system, and almost all of the 5-HT is inactived by endothelial cells in liver and lungs except that a small part of 5-HT is reabsorbed and stored in platelets. 5-HT binding to its receptor produces a variety of biological effects, and now the widely accepted classification of 5-HT is that 5-HT have been divided into seven receptor classes, wherein 5-HT2 is a member of the G protein receptor super family which contains 5-HT2A, 5-HT2B, 5-HT2c and distributed in the vessel wall, vascular endothelial cells, platelets, kidneys and other tissues or organs. 5-HT system has been implicated with the pathophysiology of pulmonary arterial hypertension for many years, and some studies indicated that 5-HT2 receptor antagonist can specifically bind with 5-HT2 receptor to inhibit the action of 5-HT and plays a series of biological effects. And specially, the study of 5-HT in vascular endothelial protection, prevention of the proliferation of vascular smooth muscle, coronary heart disease and other aspects has been the concern of the medical workers. Currently, several kinds of serotonin (5-HT) receptor antagonist and serotonin transporters blockers are been studied for treating PAH, although these clinical trials have not yet to be completed and drug hasn't listed, the related new drug research and development is becoming a hotspot for the PAH treatment, which has important clinical and practical significances.